Multi-part substitution infusion fluids and matching anticoagulants

ABSTRACT

A multi-part substitution infusion fluid for an extracorporeal blood treatment and methods for using same are provided. Generally, the multi-part substitution fluid comprises a first solution composed of electrolites but without divalent cations and a second solution comprising divalent cations. Another embodiment includes a third solution comprising a matching citrate/citric acid anticoagulant. The described methods of using the multi-part substitution infusion fluids significantly reduce risks associated with various extracorporeal blood treatments.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/742,137 filed Dec. 19, 2003, now U.S. Pat. No. 7,186,420, which is acontinuation-in-part of related U.S. patent application Ser. No.10/742,137 filed Dec. 19, 2003, which is a continuation-in-part ofrelated U.S. patent application Ser. No. 09/959,543 filed Oct. 23, 2001,which is a Section 371 filing of PCT/EP00/03583 filed Apr. 20, 2000,which claims priority to EP 99201302.9 filed Apr. 26, 1999 the entirecontents of which are all herein incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The invention relates to Multi-part substitution infusion fluids usefulfor continuous extracorporeal treatment of blood and matchingcitrate/citric acid anticoagulant solutions. Among these treatmentscontinuous-veno-venous hemofiltration (CVVH) is a widely used technique.

BACKGROUND OF THE INVENTION

Extracorporeal blood treatment is a therapy that is widely used forcritically ill patients. Many of these patients suffer from acute renalfailure and are treated with continuous renal-replacement therapy(CRRT), a form of extracorporeal blood treatment that is normallyperformed in the Intensive Care Units (ICU's). In ICUs, CRRT therapy ismostly employed as so-called continuous veno-venous hemofiltration(CVVH) and to a lesser extent as continuous arterio-venoushemofiltration (CAVH) or continuous veno-arterial hemofiltration (CVAH),all of which represent various forms of hemofiltration.

Another form of renal replacement therapy that can be used for patientswith renal failure in ICU's is hemodialysis. Pure hemofiltration as arenal-replacement therapy in an ICU can also be combined withhemodialysis as so-called continuous-Veno-venous-hemodiafiltration(usually abbreviated as CVVHD or CVVHDF) or ascontinuous-arterio-venous-hemodiafiltration (usually, abbreviated asCAVHD or CAVHDF). The addition of hemodialysis to a hemofiltrationtherapy implies the addition of a hemodialysis fluid (a so-called‘dialysate’) flow, making such combined therapy forms more complex thanpure hemofiltration. Hemodialysis usually can only be applied for a fewhours per day and is much less effective than pure hemofiltration.

Typically, in extracorporeal treatments such as CVVH, CAVH, CVVHD,CAVHD, CVAH, and hemodialysis an artificial kidney is used. This kidneymay be formed of hollow-fibers or of plates, and is connected to apatient's bloodstream by an extracorporeal circuit. In CVVH(D) thesupply from and return to the blood of the patient is made via twovenous accesses, using a blood pump to provide the driving force for thetransport of blood from the patient into the artificial kidney and backto the patient. In CAVH(D), the access which provides the supply ofblood to the artificial kidney is made via an artery and the return ofthe blood to the patient is made via a venous access. In this set-up inmost cases blood pumps are generally not used because the arterial bloodpressure is used to provide the driving force for the transport ofblood, which implies that the blood flow rate directly varies with theblood pressure. Because of better control of blood flow, no risk ofarterial catheter-related complications, and higher treatmentefficiency, CVVH is preferred above CAVH as renal replacement therapy inICU's.

In CVVH the patient's blood is passed through the artificial kidney,over a semipermeable membrane. The semipermeable membrane selectivelyallows plasma water and matter in the blood to cross the membrane fromthe blood compartment into the filtrate compartment, mimicking thenatural filtering function of a kidney. This leads to a considerableloss of fluid from the blood, which is removed as the filtrate in theartificial kidney. Every liter of filtrate fluid that is removed in theartificial kidney, contains a large fraction of the molecules that aredissolved in the plasma, like urea, creatinine, phosphate, potassium,sodium, glucose, amino acids, water-soluble vitamins, magnesium,calcium, sodium, and other ions, and trace elements. The fraction of themolecules that passes the semipermeable membrane depends mainly on thephysico-chemical characteristics of the molecules and the membrane. Inorder to keep the blood volume of the patient at a desired (constant)level, a substitution infusion fluid is added to the blood stream in theextracorporeal circuit, after is has passed through the artificialkidney and before it re-enters the patient's vein.

In a normal CVVH procedure, approximately 50 liters of filtrate areremoved per 24 hours, and approximately the same amount of substitutioninfusion fluid is added into the return of blood side of theextracorporeal circuit. The substitution infusion fluid commonly used isconventional infusion fluid consisting of a physiological salinesolution generally only containing about 140 mmol/L of sodium ions, 1.6mmol/L of calcium ions, 0.75 mmol/L of magnesium ions, 36 mmol/L ofbicarbonate ions, and 110 mmol/L of chloride ions. All forms ofhemodialysis or hemodiafiltration therapies are characteristicallydifferent from pure hemofiltration by the use of a dialysate fluid flowalong the semipermeable membrane side opposite to the blood side. Theremoval of molecules (clearance) in hemodialysis is dependent on thediffusion of molecules through the semipermeable membrane, while inhemofiltration the molecules are removed by pulling the plasma throughthe semipermeable membrane, a process that is named convection. Withconvection the fraction of larger molecules that passes through thesemipermeable membrane is much larger than with diffusion. Therefore,all hemodialysis forms of treatment are much less effective in removinglarger molecules than pure hemofiltration.

In order to prevent coagulation of the blood during hemofiltration,usually an anticoagulant is added to the blood in the extracorporealcircuit before it enters the artificial kidney. In the past, heparin orfractionated heparin was often used for this purpose. A drawback of theuse of heparin, however, is that this use leads to systemicanticoagulation (i.e., anticoagulation of all blood including thatwithin the patient), giving rise to the risk of the occurrence ofserious bleeding complications, particularly in seriously ill patients.

Instead of heparin, citrate ions can be used as anticoagulant, as hasbeen proposed for the first time by Pinnick et al., New England Journalof Medicine 1983, 308, 258-263, for hemodialysis. Citrate ions, usuallyadded in the form of trisodium citrate, are believed to bind freecalcium ions in the blood, which have a pivotal role in the coagulationcascade.

Citrate ions, added to the blood into the extracorporeal circuit beforeit enters the artificial kidney, are only active as an anticoagulant inthe extracorporeal circuit, whereby the risk of bleeding complicationsdue to systemic anticoagulation is avoided. When citrate ions areapplied during hemodialysis forms of treatment, a calcium-andmagnesium-free substitution fluid or dialysate is required. Therefore,the application of citrate ions during hemodialysis is more complex thanduring pure hemofiltration.

Citrate ions are mainly metabolized in skeletal muscle and liver tissue.Only in cases of severe hepatic failure combined with severe shock, orof certain (rare) metabolic diseases, the metabolism of citrate may runshort, leading to too high citrate concentrations in the systemic bloodcirculation, which on its turn may endanger the patient. Accordingly,citrate ions are an attractive anticoagulant for use in purehemofiltration procedures, especially for use in CVVH treatment in ICUpatients.

During hemofiltration, part of the citrate ions is removed from theblood in the artificial kidney. The citrate ions that flow over into thesystemic circulation of the patient, are rapidly metabolized tobicarbonate ions in skeletal muscle and liver tissue (about 2.8molecules bicarbonate are made from 1 citrate molecule). Becausetrisodium citrate contains on a molar basis three times as many sodiumions as citrate ions, the sodium ions that flow over into the systemiccirculation of the patient significantly increases the blood sodiumconcentration. As a result, hypematremia and/or an abnormal increase inbicarbonate ions (metabolic alkalosis) may occur Therefore, replacementof a part of the trisodium citrate by citric acid may reduce the sodiumload and, by its acid component, neutralizes part of the bicarbonategenerated. Accordingly, a mixture of trisodium citrate with citric acid,is a more attractive anticoagulant for use in hemofiltration proceduresthan trisodium citrate alone, especially for use in CVVH treatment inICU patients.

Because citrate ions bind to positively charged metal ions like calcium,magnesium, iron, zinc, copper, and manganese, these ions are also partlyremoved in the artificial kidney, leading to a net removal of calciumand magnesium ions and other metal ions from the patient's blood. As aresult, hypocalcemia and/or hypomagnesemia and/or shortages of othermetal ions may be induced in the patient. Especially the hypocalcemia,hypomagnesemia, and/or metabolic alkalosis, may induce life-threateningcomplications in the patient.

The process of hemofiltration, induces a net removal of phosphate andpotassium ions, trace elements, water-soluble vitamins, amino acids andof glucose in the artificial kidney. For example, when during CVVH 50liters of plasma filtrate per day are removed, it usually contains allof the dissolved urea, creatinine, sodium, potassium, and bicarbonate,and significant amounts of the other dissolved molecules like phosphate,calcium salts, trace elements, water-soluble vitamins, amino acids,and/or glucose. This may lead to significant degrees of hypovolemia,hypophosphatemia, hypokalemia, and shortages of trace elements,water-soluble vitamins, amino acids, and/or glucose, with the risk ofdeteriorating the patient's condition. Especially the hypophosphatemiamay also induce life-threatening complications in the patient. In orderto prevent these complications from occurring, it is crucial to returnan appropriate volume of substitution infusion fluid per unit of time,containing appropriate amounts of the removed molecules that are neededby the patient.

SUMMARY OF THE INVENTION

The present invention provides one or more substitution infusion fluidscombined with matching anticoagulant citrate solutions useful forextracorporeal blood treatments such as, but not limited to, all formsof pure hemofiltration, hemodialysis, hemodiafiltration, combinations ofhemofiltration and oxygenation, systemic rewarming, and continuousplasma filtration absorption (CPFA).

In one embodiment of the present invention a single substitutioninfusion fluid comprising sodium ions, calcium ions, magnesium ions,potassium ions, and optionally glucose, acetate ions and bicarbonateions in provided.

In another embodiment of the present invention a two part substitutioninfusion fluid is provided comprising a first substitution infusionfluid comprising electrolytes but excluding magnesium and calcium, and asecond aqueous substitution infusion fluid comprising calcium ions andmagnesium ions. As used herein electrolytes shall include but are notlimited to any one or more of the following: potassium, sodium, chlorideand phosphate ions. In an alternative embodiment glucose, potassiumand/or phosphate can be included in the first or second substitutioninfusion fluid.

Both the single and two part substitution infusion fluids of the presentinvention are generally used with a matching citrate anticoagulantsolution comprising trisodium citrate and citric acid.

In one embodiment of the present invention' a two part aqueoussubstitution infusion fluid for an extracorporeal blood treatment isprovided having a first aqueous substitution infusion fluid comprisingfrom about 70 mmol/L to about 130 mmol/L sodium ion, about 0.01 mmol/Lto about 5 mmol/L of potassium ion, from about 100 mmol to 150 mmol/Lchloride ion, about 0.01 mmol to about 1.5 mmol/L phosphate ion andoptionally 2 mmol/L to approximately 11.5 mmol/L glucose together with asecond aqueous infusion fluid comprising about 10 mmol/L to 35 mmol/Lcalcium ion, about 2.5 mmol/L to 20 mmol/L magnesium ion and optionallybetween 0.4 and 0.8 mmol/L of phosphate ions.

Optionally, either substitution infusion fluids of the present inventionmay also contain between 1.9 and 2.3 mmol/L of calcium ions and/orbetween 0.5 and 1 mmol/L of magnesium ions.

In another embodiment of the present invention the two part aqueoussubstitution infusion fluid may also contain iron ions, and/or zincions, copper ions, manganese ions, water-soluble vitamins, amino acidsand/or other trace elements.

The present invention may also include a matching citrate anticoagulantsolution comprising between 19 and 135 mmol/L of citric acid; andbetween 80 and 550 mmol/L of trisodium citrate.

In another embodiment the matching citrate solution may containtrisodium citrate in an amount of between 106 and 290 mmol/L.

In yet another embodiment of the present invention the matching citratesolution may comprises about 38-39 mmol/L of citric acid and about211-212 mmol/L of trisodium citrate.

Another aspect of the present invention includes an extracorporeal bloodtreatment including the steps of providing blood to an artificial kidneyvia an extracorporeal circuit; adding a citrate/citric acidanticoagulant to the blood prior to entering the artificial kidney,filtering the blood using a semi-permeable membrane, adding asubstitution fluid back to the filtered blood, returning the filteredblood containing the substitution fluid hack to the patient wherein saidanticoagulant and said substitution fluid are matched to provide forconsistent concentrations of systemic electrolytes in a patientundergoing extracorporeal blood treatment.

Also provided with the present invention is a kit for performing anextracorporeal blood treatment including a citrate/citric acidanticoagulant composition and a matched substitution fluid that providefor consistent concentrations of systemic electrolytes in a patientundergoing extracorporeal blood treatment.

Another embodiment of the present invention is a three part system forhemofiltration of blood including a first aqueous substitution infusionfluid comprising sodium ions, potassium ions, chloride ions andphosphate ions together with a second aqueous infusion fluid comprisingcalcium ions and magnesium ion together with a matching citrate/citricacid anticoagulant solution.

These and other embodiments of the present invention will be more fullyunderstood by reference to the figures and the detailed description thatfollow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically depicts an exemplary extracorporeal treatmentprocess of the present invention.

FIG. 2 schematically depicts an exemplary alternative extracorporealtreatment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

As explained above, extracorporeal treatments for use according to thepresent invention includes but is not limited to variousrenal-replacement therapies such as pure hemofiltration (CVVH, CAVH,CVAH) hemodialysis, hemodiafiltration, as well as combinations ofhemofiltration and oxygenation, systemic rewarming, and CPFA. As usedherein the term “pure hemofiltration” shall be used to distinguishhemofiltration from hemodiafiltration. Hemodiafiltration combinesdialysis with hemofiltration. The present invention providescompositions and methods for preventing complications associated withcertain extracorporeal treatments such ascontinuous-veno-venous-hemofiltration procedures, especially whencitrate ions are used as anticoagulant.

Surprisingly, it has been found that these goals may be reached bymaking use of a substitution infusion fluid of a specific composition.The term “substitution infusion fluid” as used herein may also bereferred to as “replacement fluid” or “substitution fluid.” Nodistinction between the claimed substitution infusion fluids and other“replacement fluids” or “substitution fluids” is inferred by the presentinventor's choice of terms. Accordingly, in one embodiment the presentinvention relates to an aqueous substitution infusion fluid forextracorporeal treatments comprising (as used herein mmol/L is“millimoles” of the salt or ion per liter of aqueous substitutioninfusion fluid) between 0.2 and 1, preferably between 0.5 and 0.9 mmol/Lof dihydrogen phosphate ions; between 70 and 130, preferably between 70and 120 mmol/L of sodium ions; between 1.6 and 2.6, preferably between1.9 and 2.4 mmol/L of calcium ions; between 0.25 and 1.25, preferablybetween 0.5 and 1.0 mmol/L of magnesium ions; between 1 and 4,preferably between 1.8 and 3.5 mmol/L of potassium ions; between 3 and11.5, preferably between 5.5, and 7.5 mmol/L of glucose; below 5.5mmol/L, preferably between 0 and 3.1 mmol/L of acetate ions; and below5.5. mmol/L, preferably between 0 and 3.1 mmol/L of bicarbonate ions.This substitution infusion fluid is usually supplemented with chlorideions to achieve a neutral electrochemical balance.

In another embodiment of the present invention the calcium and/ormagnesium may be removed form the substitution infusion fluid andprovided as a separate infusion fluid. This embodiment has the advantageof being more stable during long term storage than substitution infusionfluids that combine calcium and magnesium with other electrolytes,anions and salts thereof. Moreover, calcium and magnesium-free infusionfluids are more readily adaptable to procedures wherein the substitutionfluid is infused prior to filtration where versus post-filtrationinfusion.

Persons having ordinary skill in the art of extracorporeal bloodtreatments will realize that balancing fluid input and output is oftenrequired to prevent hypertension or hypertension as well as othersyndromes associated with dehydration or over-hydration. The multi-partsubstitution fluids of the present provide a convenient means forachieving optimum fluid balance. The physician having ordinary skill isable to closely monitor fluid intake and electrolyte balance andincrease or decrease the total volume of substitution infusion fluidsprovided the patient as needed. Furthermore, the ordinary skilledphysician will combine his/her clinical judgment with laboratory testresults. Moreover, the majority of modern extracorporeal blood treatmentdevices, including but not limited artificial kidneys, have fluidbalances integrated into their delivery systems that will alarm anattending physician or nurse should fluid input exceed fluid output orvisa versa. Moreover, most extracorporeal blood treatment devices arefully programmable allowing for precise fluid balance regulation andcontrol.

For example, and not intended as a limitation, a two-part aqueoussubstitution infusion fluid made in accordance with the teachings of thepresent invention may include a first aqueous substitution infusionfluid having from about 70 mmol/L to about 130 mmol/L sodium ion, about2 mmol/L to about 10 mmol/L of glucose, about 0.01 mmol/L to about 5mmol/L of potassium ion, from about 100 mmol to 150 mmol/L chloride ionand about 0.01 mmol to about 1.5 mmol/L phosphate ion.

The first substitution infusion fluid described above could then be usedin combinations with a second aqueous infusion fluid having about 10mmol/L to 34 mmol/L calcium ion, about 2.5 mmol/L to 20 mmol/L magnesiumion and 30 mmol/L to about 100 mmol/L of chloride ion.

Moreover, in another embodiment the substitution infusion fluids of thepresent invention (both the one-part and two-part substitution infusionfluids) may be used with a matching citrate solution. The same citratesolution is used regardless of whether a one part or two-partsubstitution infusion fluid is used. Thus by using the specificsubstitution infusion fluid together with a matching citrateanticoagulant solution in an extracorporeal blood treatment procedure,the concentrations of potassium, phosphate, calcium, magnesium,bicarbonate ions, and glucose remain substantially within acceptableranges. In most cases, the concentrations of these ions and glucoseremain more or less constant in the systemic blood of the patientundergoing, for example, hemofiltration. Consequently, the chances ofthe occurrence of the problems encountered in hemofiltration to date aresignificantly reduced, if not eliminated altogether. Particularly, thechances of the above-indicated complications including electrolyte oracid-base abnormalities and/or sever bleeding are significantly reduced.

The substitution infusion fluids according to the present invention maybe conveniently prepared by dissolving salts in water in such amountsthat the desired concentrations are reached, as is well within theexpertise of the normal person skilled in the art. During preparation,it is desired that a sterile environment is maintained. Accordingly, thesubstitution infusion fluids preferably are sterile, according to theEuropean Pharmacopeia or United States (US) Pharmacopeia, therebyavoiding the risk of infections in a patient when the fluids are usedduring hemofiltration.

Typically, substitution infusion fluids are hypotonic. Exemplary valuesare between 200 and 270 mOsm/L. Nevertheless, it has been found that thefluid is well tolerated by patients when it is used in a hemofiltrationprocedure. It has been found that the hypotonicity is in fact beneficialby compensating for the hypertonicity induced at the arterial side ofthe extracorporeal circuit by the anticoagulant. The result is that theblood that is returned into the patient's blood stream has substantiallynormal (physiological) osmolarity.

Surprisingly, it has also been found that the prevention of theoccurrence of the above-described complications may further avoided bymaking use of a matching citrate anticoagulation fluid in accordancewith the teachings of the present invention. Accordingly, the inventionalso relates to an aqueous citrate anticoagulation fluid forextracorporeal treatments comprising between 19 and 135 mmol/L of citricacid; and between 80 and 550 mmol/L of trisodium citrate, preferablybetween 106 and 290 mmol/L of trisodium citrate.

By using the citrate anticoagulation infusion fluid according to theinvention in an extracorporeal treatment, the blood is effectivelyanticoagulated within the extracorporeal circuit and not within thesystemic circulation of the patient and the concentrations of sodium,calcium, magnesium, and bicarbonate ions remain substantially withinranges of which it is accepted that they lead not to unacceptable riskof complications within the patient. This citrate anticoagulant solutioncould be used in any appropriate extracorporeal blood treatment and isespecially useful during all kinds of pure hemofiltration procedures incombination with the matching substitution infusion fluids according tothe present invention. In one exemplary embodiment, such solution mayinclude, for example, a one part substitution infusion fluid comprisingabout 117 mmol/L-129 mol/mL of sodium ions, about 2.3 mmol/L of calciumions, about 2.5 mmol/L-3.0 mmol/L of potassium ions, about 0.8 mmol/L ofphosphate ions, about 0.9 mmol/L of magnesium ions, about 6.5 mmol/L-7.1mmol/L of glucose, less than 5.5 mmol/L of acetic acid, and chlorideions to keep electrochemical balance. Moreover, it may be desirable toadd about 0.0 mmol/L to about 5.5 mmol/L of acetate ion to prevent theformation of calcium phosphate sedimentation in the one partsubstitution infusion fluid. In other embodiments, for example, glucoseand/or acetic acid and/or phosphate can be omitted, as well asconcentrations of other ingredients can be adjusted up or down asnecessary.

In another embodiment of the present invention a two-part substitutioninfusion fluid is used in combination with the matching citratesolution. Such two-part substitution infusion fluid for use in variousextracorporeal treatments will comprise a first infusion substitutionfluid including electrolytes, but excluding calcium and magnesium, and asecond infusion fluid comprising calcium and magnesium. In one example,the two part substitution infusion fluid may comprise a firstsubstitution infusion fluid comprising between 70 and 130 mmol/L sodium,between 0.01 and 5 mmol/L potassium, up to 150 mmol/L chloride andbetween 0.01 and 1.5 mmol/L phosphate; and a second substitutioninfusion fluid may comprise between 10-35 mmol/L calcium and between 2.5to 20 mmol/L magnesium ions. Optionally, the first substitution infusionfluid may also comprise between 2 and 11.5 mmol/L of glucose. In otherembodiments, between 0.4 and 0.8 mmol/L of phosphate ions may be addedto either the first of the second solution.

In one embodiment of the present invention calcium ion provided in theform of a calcium salt selected from the group consisting of calciumglubionate, calcium chloride and calcium gluconate and magnesium ion isprovided in the form of a magnesium salt selected from the groupconsisting magnesium sulfate, magnesium chloride, magnesium glubionateand magnesium gluconate.

In a preferred embodiment a two part substitution infusion fluids isused in combination with a matching anticoagulant citrate solution. Thetwo part substitution infusion fluid comprising a first substitutioninfusion fluid comprising about 117 mmol/L sodium, about 6.5 mmol/Lglucose, about 2.6 mmol/L potassium, about 115 mmol/L-140 mmol/Lchloride and about 0.8 mmol/L phosphate; and a second substitutioninfusion fluid comprising about 15-25 mmol/L calcium, about 10-12 mmol/Lmagnesium ions. In a preferred embodiment, the second substitutioninfusion fluid comprises from about 14-16 mmol/L calcium and from about10-11 mmol/L magnesium.

It has been found that when a two part substation fluid of this type isused in combination with a matching solution of trisodium citrateconsisting of about 106-290 mmol/L trisodium citrate as ananticoagulant, the concentrations of the indicated ions in the patient'sblood remain substantially within the physiological range throughout theexamplary pure hemofiltration procedure.

In a preferred embodiment, the present citrate anticoagulation solutionfor pure hemofiltration treatment is an aqueous solution meeting theabove requirements, comprising about 38 mmol/L of citric acid and about212 mmol/L of trisodium citrate. This citrate anticoagulation solutionis preferably in combination with a matching two part substitutioninfusion fluid as disclosed above.

By way of example, the invention will now be described in more detailwhile referring to FIG. 1 which illustrates the process ofhemofiltration by CVVH. Referring to FIG. 1, blood is extracted from avein of a patient and transported to an artificial kidney (4, 5, 6) viathe arterial side (1) of an extracorporeal circuit (1, 2) by the drivingforce of a blood pump (14). Anticoagulant, a matching citrate solution,is added to the blood between the blood pump (14) and the artificialkidney (10). In another embodiment, the citrate anticoagulant can beadded downstream of the blood pump (14). Optionally, an additional pumpcan be used to assist the flow of the citrate anticoagulant.

In the artificial kidney, the blood is filtered over a semi-permeablemembrane (5). The filtrate is removed from the filtrate compartment ofthe artificial kidney (6) via connecting tubing (7). A pump (8) takescare of the transport of filtrate into a collection reservoir (9).

The retentate blood is transported back from the retentate compartmentof the artificial kidney (4) to the patient's blood stream via thevenous side (return side) of the extracorporeal circuit (2), afterpassage of an airtrap (3). The airtrap serves to remove all air bubblesfrom the blood before it is returned into the patient's blood stream.Preferably, the blood is returned into the patient's blood stream at thesame place as at which it was extracted, e.g., by way of a double-lumenvenous catheter.

Before the blood is returned to the patient, the substitution infusionfluid is added from a reservoir (11), via a pump (12) and a heater (13).The heater ensures that the fluid ultimately entering the patient's bodyis substantially equal to the patient's body temperature, thus makingthe entire procedure substantially less uncomfortable.

FIG. 2 depicts another embodiment wherein a two part substation infusionfluid is used necessitating two reservoirs (11) and (15) which supplyfirst substitution infusion fluid and the second substation infusionfluid via separate pumps (12) and (16) and heaters (13) and (18).

During the procedure, the amount of filtrate collected in the reservoir(9) is determined accurately, e.g., by weighing (device not shown). Theamount of substitution infusion fluid added to the blood is adapted tothis amount. This makes it possible to make sure that an exactlypredetermined volume of fluid is returned to the patient's body (2),matching the originally extracted volume therefrom or adapted to thefluid balance needed in a particular patient (1). The flow through pumps(8) and (12) or (16) are accordingly precisely adjusted to one another.Typically, the substitution infusion fluid is administered (infused)into the blood at a rate of between 8 and 80 ml/min per 200 ml/minblood. In practice, alerting means, such as an audible alarm, are oftenprovided for alerting nursing personnel should an interruption of theblood, filtrate, or substitution flow occur. Typically, said specificanticoagulation fluid of trisodium citrate and citric acid is infusedinto the blood at a rate of between 1.3 and 4 ml/min per 200 mL/minblood.

1-24. (canceled)
 25. A two part system for extracorporeal bloodtreatment comprising: a first substitution infusion fluid comprisingelectrolytes; and a second aqueous substitution infusion fluidcomprising calcium ions, magnesium ions, glucose, potassium ions andphosphate ions.
 26. The two part system for extracorporeal bloodtreatment of claim 25, wherein the first aqueous infusion fluid and thesecond aqueous infusion fluid comprise sodium ions.
 27. The two partsystem for extracorporeal blood treatment of claim 25, wherein thesecond aqueous infusion fluid comprises from about 70 mmol/L to about130 mmol/L of the sodium ion.
 28. The two part system for extracorporealblood treatment of claim 25, wherein the second aqueous infusion fluidcomprises from about 0.01 mmol/L to about 5 mmol/L of the potassium ion.29. The two part system for extracorporeal blood treatment of claim 25,wherein the second aqueous infusion fluid comprises from about 100mmol/L to about 150 mmol/L of the chloride ion.
 30. The two part systemfor extracorporeal blood treatment of claim 25, wherein the secondaqueous infusion fluid comprises from about 0.01 mmol/L to about 1.5mmol/L of the phosphate ion.
 31. The two part system for extracorporealblood treatment of claim 25, wherein the second aqueous infusion fluidcomprises from about 2 mmol/L to about 11.5 mmol/L of glucose.
 32. A twopart aqueous substitution infusion fluid for an extracorporeal bloodtreatment comprising: a first substitution infusion fluid comprisingelectrolytes and phosphate; and a second aqueous substitution infusionfluid comprising calcium ions, magnesium ions, glucose and potassiumions.
 33. The two part aqueous substitution infusion fluid of claim 32,wherein the first aqueous infusion fluid and the second aqueous infusionfluid comprise sodium ions.
 34. The two part aqueous substitutioninfusion fluid of claim 32, wherein the second aqueous infusion fluidcomprises from about 70 mmol/L to about 130 mmol/L of sodium ion. 35.The two part aqueous substitution infusion fluid of claim 32, whereinthe second aqueous infusion fluid comprises from about 0.01 mmol/L toabout 5 mmol/L of the potassium ion.
 36. The two part aqueoussubstitution infusion fluid of claim 32, wherein the second aqueousinfusion fluid comprises from about 100 mmol/L to about 150 mmol/L ofthe chloride ion.
 37. The two part aqueous substitution infusion fluidof claim 32, wherein the first aqueous infusion fluid comprises fromabout 0.01 mmol/L to about 1.5 mmol/L of the phosphate ion.
 38. The twopart aqueous substitution infusion fluid of claim 32, wherein the secondaqueous infusion fluid comprises from about 2 mmol/L to about 11.5mmol/L of glucose.
 39. A substitution infusion fluid for anextracorporeal blood treatment comprising: sodium ions, calcium ions,magnesium ions, potassium ions, glucose, phosphate ions and bicarbonateions.
 40. The substitution infusion fluid of claim 39 comprising between0.2 and 1 mmol/L of dihydrogen phosphate ions, between 70 and 130 mmol/Lof sodium ions, between 1.6 and 2.6 mmol/L of calcium ions, between 0.25and 1.25 mmol/L of magnesium ions, between 1 and 4 mmol/L of potassiumions and between 3 and 11.5 mmol/L of glucose.
 41. The substitutioninfusion fluid of claim 39 comprising between 0.5 and 0.9 mmol/L ofdihydrogen phosphate ions, between 70 and 120 mmol/L of sodium ions,between 1.9 and 2.4 mmol/L of calcium ions, between 0.5 and 1.0 mmol/Lof magnesium ions, between 1.8 and 3.5 mmol/L of potassium ions andbetween 5.5. and 7.5 mmol/L of glucose.
 42. A two part system forextracorporeal blood treatment comprising: a first substitution infusionfluid comprising electrolytes; and a second aqueous substitutioninfusion fluid comprising potassium ions and phosphate ions.
 43. The twopart system for extracorporeal blood treatment of claim 42, wherein atleast one of the first substitution infusion fluid and the secondaqueous substitution infusion fluid comprises glucose.